Relevant effects of tumor necrosis factor (TNF). TNF acts on the hypothalamus to induce fever and on hepatocytes to induce an acute-phase response, mainly via interleukin (IL)-1 and IL-6, respectively (blue lines). TNF also exerts a wide variety of immunoregulatory (left) and pro-inflammatory actions: TNF is involved in the maturation of dendritic cells (DC) and activates endothelial cells (EC) and immune cells (black lines). Chronic TNF often is a survival signal (green lines) and plays a role in maintaining survival niches for long-lived plasma cells (PlasmaC). Some of these effects are indirect in part, involving cytokines such as IL-6 for B cells (B) and IL-18 for cytotoxic T cells (Tc). On the other hand, chronic TNF exposure leads to the disassembly of T-cell receptors (TCR), thus inhibiting T-cell responses, and induces the expression of anti-apoptotic proteins, inhibiting programmed cell death (red lines). Effects on many other cells, such as fibroblasts or osteoclasts, were left out because of the focus on immune regulation but are of major importance elsewhere. Ab, antibodies; Ag, antigen; C', complement; CR, complement receptors; FcR, Fc receptor; IC, immune complex; MF, macrophage; MHC, major histocompatibility complex; Th, T helper cell.